The overall goal of this proposal is to develop a novel local drug delivery system for cancer radiotherapy by direct intratumoral administration of a thermally sensitive macromolecule conjugated to a therapeutic radionuclide of interest. Thermally sensitive elastin-like polypeptides (ELPs) that spontaneously undergo a soluble-insoluble phase transition between room temperature and body temperature leading to the formation of a coacervate, gel-like phase will be designed and optimized at the molecular level via genetic engineering methods. Two innovative strategies to increase the retention of the ELPs in solid tumors beyond that provided by thermal coacervation will also be investigated: (1) Zn-mediated reversible crosslinking of ELP coacervates, and (2) binding of ELPs and their proteolytic fragments to extracellular matrix proteins. These genetically engineered ELPs will be conjugated to 131I, a therapeutic radioisotope, and infused into a tumor to spontaneously form a radioactive depot within the tumor with long in vivo retention (> 1 week) at the injection site. These polymers will be evaluated for therapeutic efficacy and immunogenic properties. We hypothesize that this local delivery approach for the targeted irradiation of solid tumors from the inside-out will enhance therapeutic efficacy by providing enhanced exposure of the radionuclide to the tumor while minimizing exposure of healthy tissues, thereby reducing systemic toxicity. Furthermore, the clinical significance of the proposed research is that it will lead to a novel, genetically engineered, nonimmunogenic injectable radionuclide deposition system that is an improvement over current brachytherapy methods.